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Rogerio C. Lilenbaum, MD, discusses molecular panels and other testing for patients with nonsquamous non-small cell lung cancer.

Molecular Testing Used for Patients With Non-Small Cell Lung Cancer

ASH 2024 Preview for Community Oncologists: The Show and After Show

The American Society of Hematology (ASH) Annual Meeting and Exposition aims to educate oncology providers across an array of hematologic malignancies, with a focus on novel agents, drugs across the FDA pipeline, and more.

, co-hosts Kristie L. Kahl and Andrew Svonavec offer a glimpse at some of the presentations guaranteed to spark one’s curiosity, spur debate, and enhance the field even further. Some key highlights include:

 Continued advancements in CAR T-cell therapy are expected to revolutionize the treatment of hematologic malignancies.

 Bispecific antibodies, such as Epcoritamab (Epkinly), offer a novel approach to target multiple antigens on cancer cells.

 The assessment of MRD is becoming increasingly important in predicting treatment response and overall survival.

Advances in Acute Lymphoblastic Leukemia (ALL)

Blinatumomab (Blincyto) in pediatric ALL:

 The addition of blinatumomab to chemotherapy has shown promise in improving disease-free survival in high-risk pediatric ALL. This combination therapy may offer a more effective treatment option for young patients.

Acalabrutinib (Calquence) in mantle cell lymphoma (MCL):

 The FDA is set to review the approval of acalabrutinib with bendamustine or rituximab (Rituxan) for previously untreated MCL, based on data from the phase 3 ECHO trial (NCT02972840).

Asciminib (Scemblix) in chronic phase chronic myelogenous leukemia (CML-CP):

 The FDA recently granted accelerated approval to asciminib for newly diagnosed CML-CP. This tyrosine kinase inhibitor has shown favorable safety and tolerability profiles.

 isn't just about data, as the duo also offers food recommendations, tourist attractions and fun activities to partake in, as well as interesting facts about San Diego.

This is just a taste of the wealth of information and inspiration waiting at the 2024 ASH Annual Meeting. Check back for future meeting previews with 

Targeted Oncology co-hosts Kristie L. Kahl and Andrew Svonavec highlight abstracts for community oncologists to look out for at the upcoming ASH Annual Meeting in San Diego, with some additional tidbits to round out the main event.

News

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

The combination of neoadjuvant pembrolizumab (Keytruda) followed by surgery and adjuvant pembrolizumab with and after postoperative radiation with or without cisplatin represents a new standard of care (SOC) for the treatment of patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC), according to data from the first interim analysis from the phase 3 KEYNOTE-689 trial (NCT03765918) presented at the 

At the July 25, 2024, data cutoff, the 12-, 24-, and 36-month event-free survival (EFS) rates in all patients from the pembrolizumab plus SOC (n = 363) vs SOC (n = 351) arms were 75.1% vs 62.5%, 65.0% vs 54.6%, and 57.6% vs 46.4%, respectively. The median EFS was 51.8 months (95% CI, 37.5-not reached [NR]) in the pembrolizumab/SOC arm compared with 30.4 months (95% CI, 21.8-50.1) in the SOC arm (HR, 0.73; 95% CI, 0.58-0.92; 

 = .0041). EFS events were observed in 37.5% vs 45.3% of patients from the pembrolizumab/SOC and SOC arms, respectively. These events specifically included death (pembrolizumab/SOC, 18.5%; SOC, 18.2%), distant progressive disease (7.2%; 14.5%), local and distant progressive disease (1.1%; 2.0%), and local progressive disease with recurrence (10.7%; 10.5%).

“Neoadjuvant and adjuvant pembrolizumab as a SOC significantly improved EFS in [patients with] resectable locally advanced head neck cancer in all 3 prespecified analysis populations,” Ravindra Uppaluri, MD, PhD, said during a presentation of the data. “The overall survival [OS] benefit did not reach statistical significance in the first interim analysis, but additional follow-up is ongoing.”

Uppaluri is the director of Head and Neck Surgical Oncology at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute and associate professor of Otolaryngology at Harvard Medical School in Boston, Massachusetts.

Background and the KEYNOTE-689 Trial Design

In October 2024, Merck, the developer of pembrolizumab, announced that 

the study had met its primary end point of EFS

 after neoadjuvant pembrolizumab followed by adjuvant pembrolizumab plus radiotherapy with or without cisplatin, along with maintenance pembrolizumab, led to a significant improvement in EFS vs SOC adjuvant radiotherapy with or without cisplatin in patients with newly diagnosed resectable stage IIA or IVA, locally advanced HNSCC.

The active-controlled, open-label study evaluated the pembrolizumab combination in treatment naive patients with newly diagnosed resectable stage IIIA or IVA, locally advanced HNSCC, including larynx/hypopharynx/oral cavity cancer (stage IIIA or IVA), oropharyngeal cancer (stage III or IVA p16–), or oropharyngeal cancer (stage III T4 N0-2 p16+).

 Patients were also required to have an ECOG performance status of 0 or 1 and tumor tissue for PD-L1 testing. Stratification factors included primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA), and PD-L1 tumor proportion score (≥ 50% vs < 50%).

Patients were randomly assigned 1:1 to receive either the pembrolizumab regimen or SOC. In the pembrolizumab arm, patients were treated with neoadjuvant pembrolizumab in 2 cycles, surgery, then adjuvant pembrolizumab in 3 cycles plus radiotherapy with or without cisplatin, and 12 cycles of pembrolizumab as maintenance therapy. Notably, pembrolizumab was administered at 200 mg once every 3 weeks. Those treated in the SOC arm received surgery and adjuvant radiotherapy with or without cisplatin. Radiation dose depended on pathological risk, which included low risk, high risk, and gross residual disease. Patients from the pembrolizumab and SOC arms received 60 Gy in 30 fractions if they were low risk, 66 Gy in 33 fractions if high risk, and 50 Gy in 35 fractions if they had gross residual disease. 

Similarly, the 3 cycles of cisplatin were administered at 100 mg/m

 once every 3 weeks, regardless of pathological risk in either arm.

The primary end point was EFS per RECIST 1.1 criteria by blinded independent central review (BICR). Secondary end points included major pathological response (mPR), defined as 10% or less residual invasive squamous cell carcinoma in resected primary tumor and all sampled regional lymph nodes by blinded independent pathologist review (BIPR), OS, and safety.

Among the pembrolizumab/SOC and SOC arms, respectively, the median age was 60.0 years (range, 29-82) and 61.0 years (range, 22-87), and the majority of patients were male (78.8%; 78.9%). Of note, most were reported to be current or former smokers (80.7%; 76.1%), and currently consume alcohol (68.9%; 67.8%). The primary tumor sites included the oral cavity (pembrolizumab/SOC, 60.3%; SOC, 60.7%), larynx (22.3%; 20.8%), hypopharynx (7.7%; 7.4%), oropharynx (9.6%; 10.8%), and missing (0%; 0.3%). Positive HPV status was reported in 3.3% vs 4.3% of patients, respectively. Additionally, 64.5% and 65.8% of patients had a PD-L1 CPS of 10 or greater in the respective arms; 95.6% and 95.4% had a PD-L1 CPS of 1 or greater.

Each subgroup demonstrated favorability towards the pembrolizumab combination compared with the SOC.

At the data cutoff, the 12-month EFS rate in the population with a PD-L1 combined positive score (CPS) of 10 or greater was 74.0% vs 60.0% in the pembrolizumab plus SOC (n = 234) and SOC alone (n = 231) arms, respectively. The respective EFS rates at 24 and 36 months were 65.1% vs 53.2% and 59.8% vs 45.9%. Of note, the median EFS was 59.7 months (95% CI, 41.1-NR) in the pembrolizumab/SOC arm compared with 26.9 months (95% CI, 18.3-51.5) in the SOC alone arm (HR, 0.66; 95% CI, 0.49-0.88; 

 = .0022). EFS events occurred in 36.3% and 46.3% of patients from the respective arms, including death (pembrolizumab/SOC, 18.4%; SOC, 16.0%), distant progressive disease (6.4%; 16.9%), local and distant progressive disease (0.9%; 0.9%), and local progressive disease with recurrence (10.7%; 12.6%).

Among patients with a CPS of 1 or greater, the 12-, 24-, and 36-month EFS in the pembrolizumab/SOC (n = 347) and SOC (n = 335) arms were 74.8% vs 61.3%, 64.6% vs 53.4%, and 58.2% vs 44.9%, respectively. The median EFS was 59.7 months (95% CI, 37.9-NR) compared with 29.6 months (95% CI, 19.5-41.9), respectively (HR, 0.70; 95% CI, 0.55-0.89; 

 = .0014). EFS events in this population occurred in 36.9% and 46.6% of patients from the respective arms, including death (pembrolizumab/SOC, 18.2%; SOC, 18.5%), distant progressive disease (6.9%; 15.2%), local and distant progressive disease (1.2%; 1.8%), and local progressive disease with recurrence (10.7%; 11.0%).

The mPR rates in the CPS of 10 or greater population were 13.7% (95% CI, 9.5%-18.8%) vs 0% (95% CI, 0%-1.6%), in the pembrolizumab/SOC and SOC arms, respectively, with an estimated difference of 13.7% (95% CI, 9.7%-18.7%; 

 < .00001). In the CPS of 1 or greater population, the mPR rates were 9.8% (95% CI, 6.9%-13.4%) vs 0% (95% CI, 0-1.1%). The estimated difference was 9.8% (95% CI, 7.0%-13.3%; 

 < .00001). Among all patients from both arms, the mPR rates were 9.4% (95% CI, 6.6%-12.8%) vs 0% (95% CI, 0-1.0), with an estimated difference of 9.3% (95% CI, 6.7%-12.8%; 

Regarding OS in the CPS of 10 or greater population, the 12-, 24-, and 36-month OS rates in the pembrolizumab/SOC and SOC arms, respectively, were 85.8% vs 77.8%, 74.8% vs 67.1%, and 68.2% vs 59.2%. OS events were reported in 31.2% vs 38.5% of patients, and the median OS was NR (95% CI, NR-NR) vs 61.8 months (95% CI, 49.2-NR; HR, 0.72; 95% CI, 0.52-0.98; 

The median duration of therapy in the as-treated population was 9.1 months (range, 0.03-22.3) vs 2.9 months (range, 0.03-7.2) in the pembrolizumab/SOC (n = 361) and SOC (n = 315) arms, respectively. Treatment-related adverse effects (TRAEs) included those that led to discontinuation (pembrolizumab/SOC, 17.7%; SOC, 12.4%), serious TRAEs (19.1%; 10.5%), and death (1.1%; 0.3%). Any-grade TRAEs were reported in 81.4% and 81.9% of patients from the respective arms. The most common any-grade TRAEs occurring in at least 10% of patients included radiation skin injury (39.3%; 47.0%), stomatitis (38.8%; 52.1%), hypothyroidism (19.4%; 1.9%), fatigue (18.0%; 13.0%), nausea (17.7%; 21.3%), dry mouth (17.5%; 21.6%), dysgeusia (12.7%; 17.8%), decreased neutrophil count (11.6%; 18.7%), decreased lymphocyte count (11.4%; 8.9%), vomiting (10.8%; 7.9%), decreased white blood cell count (10.8%; 15.9%), dysphagia (10.2%; 15.6%), decreased weight (9.7%; 10.8%), and anemia (8.9%; 10.8%).

 Uppaluri reported research funding from Merck Sharp & Dohme LLC (MSD); research funding from Daiichi Sankyo; and consulting fees from Daiichi Sankyo, MSD, and Regeneron.

1. Uppaluri R. Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: phase 3 KEYNOTE-689 study. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT001.

2. Merck’s Keytruda (pembrolizumab) met primary endpoint of event-free survival (EFS) as perioperative treatment regimen in patients with resected, locally advanced head and neck squamous cell carcinoma. News release. Merck. October 8, 2024. Accessed April 27, 2025. 

3. Study of pembrolizumab given prior to surgery in combination with radiotherapy given post-surgery for advanced head and neck squamous cell carcinoma (MK-3475-689). ClinicalTrials.gov. Updated February 7, 2025. Accessed April 27, 2025. 

https://clinicaltrials.gov/study/NCT03765918

Pembrolizumab combo before/after surgery and radiation significantly improved event-free survival in resectable advanced head and neck cancer per KEYNOTE-689, introducing a potential new standard of care. 

Conference News

Canonical

Keytruda Plus SOC: New Standard for Advanced Head & Neck Cancer

: Could you describe the mechanism of action of amivantamab (Rybrevant) compared with other 

-targeted therapies in non–small cell lung cancer (NSCLC)?

 Amivantamab is a unique therapeutic. It has a different mechanism of action compared with EGFR-TKIs [tyrosine kinase inhibitors]. TKIs are straightforward to think about. You have binding in the membrane and essentially you have cessation of the constitutive activation of a receptor. With amivantamab, it's an EGFR and MET bispecific and the MET entity has an interesting modality potentially targeting resistance. But up front, it allows us to anchor and target 

 more directly and impacts both intercellularly and intracellularly.

It works by 3 different mechanisms of action. First and foremost, you get standard ligand blocking, and that happens in the cell surface. Then you also get receptor internalization and degradation. The reason I became excited about this compound early on was this immunotherapeutic-type activity. All patients with 

-mutant lung cancer are going to have resistance at some point to their TKI, whatever generation it is…. This is an agent that potentially has both antibody-dependent cellular trobocytosis as well as antibody-dependent cellular cytotoxicity. By binding the FC receptor, we can bring natural killer cells and macrophages in proximity to the tumor cells, leading to cell death.

We do this in this setting in combination with lazertinib [Lazcluze]. Lazertinib is essentially, in my mind, equivalent to osimertinib [Tagrisso]. It is a third-generation EGFR-TKI. It was approved outside the United States in South Korea, but now [is approved] in the United States in combination with amivantamab.

During a Case-Based Roundtable® event, Joshua K. Sabari, MD, discussed the mechanism of action of amivantamab and the MARIPOSA trial in patients with EGFR-mutated non–small cell lung cancer in the first article of a 2-part series. 

Rogerio C. Lilenbaum, MD

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